FcgammaRIIB is a potent lupus susceptibility gene capable of interacting with a variety of other loci to modify both the induction and progression of autoimmune disease. Mice deficient in this molecule develop spontaneous anti-nuclear antibodies and fatal glomerulonephritis when on the C57BL/6 background. The same mutation on the BALB/c background is unremarkable, indicating the existence of suppressor loci on the BALB/c background which restrict the development of autoimmunity. We have identified a region of Chromosome 12 that is sufficient to render B6.FcgammaRIIB-/- mice resistant to lupus disease. We have identified candidate genes for this suppressor effect and are currently studying their use as possible therapies. Characterization of other genetic modifiers of lupus in the FcgammaRIIB-/- mouse model allowed us to determine that a duplication in the TLR7gene carried by the Y-chromosome in Yaa mice is sufficient to agravate autoimmune disease. Further studies using transgenic overexpression of TLR7 have shown that TLR7 is essential to regulate autoimmunity and prevent dendritic cell expansion. These mice provide a prime example of how important it is to control the expression of innate receptors. And provides a theoretical framework in which anti-viral innate responses, when not properly regulated, can result in autoreactivity and lethal inflammatory disease. We are currently studying the role of other anti-viral pathways in the initiation of systemic autoimmune disease.